FORMULATIONS ANTIFONGIGUES SOUS FORME DE GEL

ANTIFUNGAL GEL FORMULATIONS

Abrégé anglais

ABSTRACT
An antifungal gel composition, effective at 0.2-2.0% by
weight of an imidazole antifungal agent and 0.01-2.5% by
weight of a 17-ester corticosteroid antiinflammatory agent,
is provided for topical administration. This composition is
highly effective in treating fungal infections and is
capable of being stored without refrigeration for long
periods of time without losing therapeutic effectiveness and
while maintaining the uniformity and stability of the gel.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN
EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE
DEFINED AS FOLLOWS:
1. A stable gel formulation for topical administration consisting
essentially of (a) a therapeutically effective amount of a mixture of at least
one antifungal agent selected from the group consisting of: miconazole,
miconazole nitrate, clotrimazole, clotrimzole nitrate, enconazole,
enconazole nitrate, sulconazole and sulconazole nitrate with at least one
steroid selected from the group consisting of the acetate, butyrate,
valerate and propionate 17-esters of hydrocortisone, betamethasone,
cortisone and prednisone, (b) a solvent system consisting essentially of a
lower alkanol in combination with a dihydroxy alcohol or a trihydroxy
alcohol or a mixture thereof, (c) an effective amount of at least one gelling
agent selected form the group consisting of hydroxylpropyl cellulose and
hydroxyethyl cellulose, and (d) water in an amount up to about 20% by
weight, said formulation having a pH in the range of from about 3 to
about 5.
2. A gel formulation according to claim 1(a) consisting
essentially of from about 0.2% to 2% by weight of the imidazole from
about 0.01% to 2.5% by eight of the steroid: from about 30% to 65% by
weight of a lower alkanol solvent for the imidazole and the steroid: from
about 0-45% by weight of a dihydroxy alcohol solvent for the imidazole
and steroid or 0-40% by weight of a trihydroxy alcohol solvent, or a
mixture thereof; and from about 0.1% to 5% by weight of a gelling agent
selected from the group consisting of hydroxypropyl cellulose and
hydroxyethyl cellulose.
3. A gel formulation according to claim 2 comprising (a) from
about 0.2% to 2% by weight of an imidazole antifungal agent; (b) from
about 0.01% to 2.5% by weight of a 17-ester steroid antiinflammatory
31

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agent; (c) from about 0-20% by weight of water; (d) from about 30-65% by
weight of a lower alkanol solvent for the imidazole and 17-ester steroid;
(e) from about 0-45% by weight of a dihydroxy alcohol solvent for the
imidazole and 17-ester steroid; and (f) from about 0.1-5% by weight of a
gelling agent selected from the hydroxypropyl cellulose and hydroxyethyl
cellulose.
4. A gel formulation according to claim 2 comprising (a) from
about 0.2% to 2% by weight of an imidazole antifungal agent; (b) from
about 0.01% to 2.5% by weight of a 17-ester steroid antiinflammatory
agent; (c) from about 0-20% by weight of water; (d) from about 30-65% by
weight of a lower alkanol solvent for the imidazole and 17-ester steroid;
(e) from about 0-40% by weight of a trihydroxy alcohol solvent for the
imidazole and 17-ester steroid; and (f) from about 0.1-5% by weight of a
gelling agent selected from hydroxypropyl cellulose and hydroxyethyl
cellulose.
5. A gel formulation of any one of claims 1 to 4 which further
contains up to about 30% by weight of an emollient soluble in the gel
vehicle.
6. A gel formulation of any one of claims 1 to 4 which further
contains an effective amount of a preservative.
7. A gel formulation of any one of claims 1 to 4 which further
contains a fragrance.
8. A stable gel formulation for topical administration consisting
essentially of (a) from about 0.2-2% by weight of one or more imidazole
antifungal agents selected from the group consisting of miconazole,
miconazole nitrate, clotrimazole, clotrimazole nitrate, econazole, econazole

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nitrate, sulconazole and sulconazole nitrate; (b) from about 0.01%-2.5% by
weight of and at least one 17-ester steroid selected from the group
consisting of the 17-ester acetates, butyrates, valerates, and propionates of
hydrocortisone, betamethazone, cortisone, and prednisone; (c) from about
30-65% by weight of a lower alkanol solvent for the imidazole and 17-ester
steroid; (d) from about 0-45% by weight of a dihydroxy alcohol solvent for
the imidazole and 17-ester steroid; (e) from about 0-40% by weight of a
trihydroxy alcohol solvent for the imidazole and 17-ester steroid; (f) about
20% by weight or less of water; and (g) from about 0.1-5% by weight of a
gelling agent selected from hydroxypropyl cellulose and hydroxyethyl
cellulose, said formulation having a pH in the range of about 3 to about 5.
9. A gel formulation according to claim 8 which further
contains about 30% or less by weight of an emollient soluble in the gel
vehicle.
10. A gel formulation according to claim 8 or 9 which further
contains an effective amount of a preservative.
11. A gel formulation according to claim 8 or 9 wherein the
lower alkanol solvent is ethanol, isopropanol or a mixture thereof.
12. A gel formulation according to claim 8 or 9 wherein the
dihydroxy alcohol solvent is propylene glycol, 2-ethyl-1,3-hexanediol, or a
mixture thereof.
13. A gel formulation according to claim 8 or 9 wherein the
trihydroxy alcohol solvent is 1,2,6-hexanetriol.
14. A gel formulation according to claim 9 wherein the emollient
is isopropyl myristate, PPG-5-ceteth-20, PG dioctanate, methyl gluceth-10,

-34 -
isodecyl neopentanoate, glycerin, mineral oil, methyl gluceth-20, PPG-10
methyl glucose ether, PPG-20 methyl glucose ether, or a mixture thereof.
15. A gel formulation according to claim 14 wherein the
emollient is isopropyl myristate, PPG-5-ceteth-20, PPG-20 methyl glucose
ether, or a mixture thereof.
16. A stable aqueous gel formulation for topical administration
having substantially the following formula:
<IMG>
17. A gel formulation according to claim 10 wherein the lower
alkanol solvent is one or more of ethanol and isopropanol.
18. A gel formulation according to claim 10 wherein the
dihydroxyl alcohol solvent is one or more of propylene glycol and 2-ethyl-
1,3-hexanediol.
19. A gel formulation according to claim 11 wherein the
dihydroxyl alcohol solvent is one or more of propylene glycol and 2-ethyl-

-35-
1,3-hexanediol.
20. A gel formulation according to claim 10 wherein the
trihydroxy alcohol is 1,2,6-hexanetriol.
21. A gel formulation according to claim 11 wherein the
trihydroxy alcohol is 1,2,6-hexanetriol.
22. A gel formulation according to claim 12 wherein the
trihydroxy alcohol is 1,2,6-hexanetriol.
23. A gel formulation according to claim 10 which further
contains an emollient which is one or more of isopropyl myristate, PPG-5-
ceteth-20, PG dioctonate, methyl gluceth-10, isodecyl neopentanoate,
glycerin, mineral oil, methyl gluceth-20, PPG-10 methyl glucose ether and
PPG-20 methyl glucose ether.
24. A gel formulation according to claim 11 which further
contains an emollient which is one or more of isopropyl myristate, PPG-5-
ceteth-20, PG dioctonoate, methyl gluceth-10, isodecyl neopentonoate,
glycerin, mineral oil, methyl gluceth-20, PPG-10 methyl glucose ether and
PPG-20 methyl glucose ether.
25. A gel formulation according to claim 12 further containing
an emollient which is one or more of isopropyl myristate, PPG-5-ceteth-20,
PG dioctonate, methyl gluceth-10, isodecyl neopentonoate, glycerin,
mineral oil, methyl gluceth-20, PPG-10 methyl glucose ether and PPG-20
glucose ether.
26. A gel formulation according to claim 13 further containing
an emollient which is one or more of isopropyl myristate, PPG-5-ceteth-20,

-36-
PG-dioctonate, methyl gluceth-10, isodecyl neopentonoate, glycerin,
mineral oil, methyl gluceth-20, PPG-10 methyl glucose ether and PPG-20
methyl glucose ether.
27. A method of stabilizing a topical gel formulation containing
an imidazole gel and at least one 17-ester steroid and having a pH in the
range of from about 3 to about 5 comprising the step of incorporating into
the formulation a combination consisting essentially of
(a) from about 30 to about 65% by weight of a lower alkanol with
about 0 to about 0 to 85% of at least one polyol selected from the group
consisting of dihydroxy alcohols and trihydroxy alcohols; and
(b) a suitable gelling amount of hydroxyethyl cellulose or
hydroxypropyl cellulose.
28. The method of claim 27 wherein the steroid is at least one
selected from the group consisting of: the acetate, butyrate, valerate and
propionate 17 esters of hydrocortisone, betamethasone, cortisone and
prednisone.
29. The method of claim 28 wherein the imidazole is at least
one selected from the group consisting of miconazole, miconazole nitrate,
clotrimazole, clotrimazole nitrate, econazole, econazole nitrate,
sulconazole and sulconazole nitrate.
30. The method of claim 29 wherein the lower alkanol is one or
more of ethanol and isopropanol.
31. The method of claim 30 wherein the dihydroxy alcohol is one
or more of propylene glycol and 2-ethyl-1,3-hexanediol.
32. The method of claim 31 wherein the trihydroxy alcohol is

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1,2,6-hexanetriol.
33. A gel formulation of claim 6 which further contains a
fragrance.
34. A gel formulation of claim 6 which further contains up to
about 30% by weight of an emollient soluble in the gel vehicle.
35. A gel formulation of claim 7 which further contains up to
about 30% by weight of an emollient soluble in the gel vehicle.
36. A gel formulation of claim 35 which further contains an
effective amount of preservative.

Description

~319~0~
BACKGROUND OF THE INVENTION
The present invention relates to a ~table gel
formulation for the topical application of a combination of
an imidazole antifungal agent and a 17-ester steroid
antiinflammatory agent. The product is particularly suitable
for treating fungal disease~ such as tinea capitis, tinea
corporis or tinea cruris. Decomposition of the 17-ester
steroid resulting from interaction with water and the
imidazole antifungal agent during storage is drastically
reduced by the present gel formulation.
A fungus is a very small microscopic type of plant cell
which may grow on the skin and, under certain conditions,
produce an infection. Such infections cau ed by fungi, the
mycoses, are among the oldest known to man and have long
been recognized as a highly prevalent public health problem.
When the fungus infection involves the scalp, it is known as
tinea capitis; when it involves the feet it is known as
tinea pedis ~athlete's foot); when it occurs on the body it
is known as tinea corporis; and when it occurs in the groin
it is known as tinea cruris.
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1 3 ~
A variety of methods have been used for khe treatment
of fungal infections includlng the use of potassium iodide,
Whitfield's ointment, undecylenic acid, antibiotics (e.g.
nystatin and amphotericin B), griqeofulvin and the imidazole
antifungal agent~ such as miconazole, clotrimazole,
econazole and sulconazole.
Although the systemic administration of antibiotics
such as nystatin and amphotericin B has been used with some
success, the low bioavailability and systemic toxicity of
these agents have restricted their use in treating mycotic
infections.
The imidazoles are the first broad-spectrum antifungals
and are of considerable importance in clinical practice.
Their broad spectrum of antifungal activity, e~tending to
most pathogenic fungi, has provided an important advance in
antifungal th~rapy.
As used herein the term "imidazole antifun~al agent"
means any agent having an imidazole functional group in the
molecule and possessing topical antifungal activity. A large
number of suitable imidazoles ha~e been described in the
literature and are well-known to those skilled in the art.
Examples of suitable imidazole antifungal agents include
sulconazole nitrate, econazole nitrate, miconazole nitrate
and clotrimazole.
The fungal infections are commonly associated with
signs of erythema and scaling and with symptoms of itching
or painful burning. Clinical treatment for fungal disease
requires at least two to four weeks for complete relief of
symptoms. More recently, it ha~ been found that fungal
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1 3 ~
infections can be effectively treated with a combination
product containing corticosteroids and imidazole antlfungal
agents. It i~ known that the sen~itivity of fun~al organisms
varie~ with their life cycles; spores are more resistant to
treatment than are mycelia. Steroids may induce fungal
spores to produce mycelia, thereby makinq them more
sensitive to treatment. Also, steroids are known to produce
vasoconstriction at the site of application. This activity
may delay or prevent the elimination of the antifungal agent
from the application site, permitting the antifungal agent
to remain in the epidermis for longer periods of time. ~t
is therefore believed that a locally applied antiinflamma-
tory agent would offer direct and immediate relief for the
-inflammatory component of the lesion. The combination
product should then provide fast relief of symptoms and
eradicate the infection. Based on this concept, certain
combinations of an antifungal agent and an antiinflammatory
agent have recently been developed for treatment of fungal
disease. Currently, the commercially available combination
products using thi concept are Lotrisone cream
(clotrimazole l~O/betamethasone dipropionate 0.05%~,
Daktacort cream (miconazole nitrate 2y/hydrocortisone 1%)
and Canesten H~ cream (clotrimazole 1%/hydrocorti~one 1%).
Katz and other dermatologistsl'2 found that Lotrisone
cream was therapeutically and mycologically better than
clotrimazole 1% and betamethasone dipropionate 0.0~% alone.
Notwithstanding its clinical advantages, Lotrisone cream
possesses some undesirable attributes. It contains a rather
strong fluorinated steroid, betamethasone dipropionate,
which can be quite cosmetically dangerous to use in
intertrigious regions. Other undesirable attributes include
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1 3 ~
skin atrophy, rebound phenomenon and telengiectasia.
Other marketed combination products of this type, e.g.
Daktacort cream and Canesten HC cream, are combinations of
low-potency steroids and imidazole~. Such combination
products always fail to provide the fast relief of the
inflammatory symptoms which is normally desired for the
treatment of a fungal infection.
A combination of a non-halogenated mid-potency steroid
and an imidazole antifungal agent would appear to be an
ideal choice for the topical treatment of fungal disease. It
was the object of the present invention to develop such a
combination product.
The mid potency steroid used in the combination product
of the present invention is a 17-ester steroid which
possesses enhanced activity relative to the parent alcohol
but fewer undesirable side effects than the halogenated
steroids which are comparable in activity. Examples of
17-ester corticosteroids included within the scope of the
invention are hydrocortisone 17-acetate, hydrocortisone
17-butyrate, hydrocortisone 17-valerate, hydrocortisone
17-propionate, betamethasone 17-valerate, cortisone
17-acetate, prednisone 17-acetate and prednisone
17-valerate.
The 17-ester steroids per se have excellent stability
in conventional topical dosage forms. In our studies topical
dosage form are tasted for stability by determinining their
tgo% values where tgo% i8 the time in days reguired for a
dosage form to lose 10% of it3 chemical and/or biological
- 4 -

13~9~
activity. ~ 0.2% hydrocortisone 17-valerate o/w crea~ in
this test had a tgo% of 536 days at room temperature (25C
2C). U~e of a standard 10% overage of active ingredient in
the cream would mean that such a product would have an
acceptable shelf life ~time required for potency to decrease
to 90% of label strength) at room t:emperature of 1072 days
or more than 2.9 years.
A cream formulation is generally more acceptable to a
patient than other topical dosage forms, e.g. liquid,
petrolatum ointment, oil, etc., rom the point of view of
aesthetics and ease of application. Unfortunately, when one
attempts to combine a 17-ester steroid and an imidazole
antifungal agent to make a combination product as described
above, the stability of the 17-ester steroid is drastically
reduced to unacceptable levels in almost all conventional
cream formulations. To develop a cream vehicle for a
combination product of a 17-ester steroid and an imidazole,
we have prepared for stability evaluation more than 60
different types of cream vehicles including o/w creams, w/o
creams, creams with high or low petrolatum content, with low
or high surfactant content, with high or low water con~ent,
and with different propylene glycol content. Almost all
creams failed our stability test, either due to the chemical
instability of the 17-ester steroids or the physical
separation of emulsion caused by the saltin~ effect of the
imidazole salt when used in concentrations of about 1% or
more. Cream formulations often necessitate the use of
emulsifiers or ~urfactant~ to maintain their physical
stability and the use of antimicrobial preservatives to
prevent microbiological contamination. The e additives tend
to generate an undesirable environment which can accelerate
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131~1~5
the hydrolysis of 17-ester steroids and the physical
separation due to the salting out. In addltion, it iQ known
that imidazoles can also be catalysts for the hydrolysis of
esters3 7. Such degradation was in fact observed in our
preliminary studies (see Table I below).
Table 1. Degradation rates of hydrocortisone 17-valerates
(HC 17-V) in the presence of 1% imidazole~ in
various topical creams at 25~C + 2.0C.
_ _ .
Formulations k, daY 1**** tgoo/, daYs***
1. Sulconazole nitrate 1%/ 3.07 x 10 3 34
HC 17-V O.2% in agueous-
alcohol solution at
pH 4.7
2. Sulconazole nitrate 1~/ 5.96 x 10 3 18
HC 17-V 0.2% in o/w cream
at pH 4.7
3. Sulconazole nitrate 1%/ 7.40 x 10 3 14
HC 17-V O.5% in USP XXI
Oint. at 4.7
4. Sulconazole nitrate 1%/ 6.50 x 10 3 16
HC 17-V 0.2% in Carbapol*
gel
5. Sulconazole nitratP lyo/ physical
HC 17-V 0.2% in Methocel*~ separation
gel
6. Sulconazole nitrate 1%/ 2.24 x 10 3 47
HC 17-V 0.2% in pure
petrolatum base
* Trademark
** Trademark

~319~ ~
Table 1. (cont.)
Formulations k, day 1**** tgO~, day~***
7. Econazole nitrate 1~/ 1.34 x 10 2 7.8
HC 17-V 0.2% in USP XXI
hydrophilic ointment
8. Miconazole nitrate 1%/ 2.99 x 10 3.5
HC 17-V 0.2% in o/w cream
9. Miconazole nitrate 1%/ 4.28 x 10 2 2.5
HC 17-V 0.2% in USP XXI
hydrophilic ointment
10. Clotrimazole 1%/HC 17-V 4.3g x 10-3 24
0.2% in o/w cream
11. Clotrimazole 1%/HC 17-V 2.26 x 10 2 4.6
O.2% in USP XXI hydrophilic
ointment
* Carbopol gel i8 a carboxy vinyl polymer of high
molecular weight (CTFA names: carbomer-934p, -940,
-961
** Methocel gel i~ the methyl ether of cellulose (CTFA
name: methylcellulose, trade names: Methocel MC,
Cellulose M~thyl Ether).
t9o% = time required for hydrocortisone 17-valerate
activity to be reduced to 90% of original
**** k - degradation rate of hydrocortisone 17-valerate
component
Based on our studies it is believed that the necessityf using emulsifiers or surfactants in most cream
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formulations results in increased interaction of the
17-ester steroid with water and imidazole molecules, thereby
causing rapid hydrolysis of the 17 ester steroid (see Table
I, formulations 2, 3 and 7-11).
Several commonly used gel formulations prepared without
any emulsifier or surfactant and with a gelling agent
selected from a group consisting of an acidic carbo~y
polymer, such as those available under the trade names
Carbopol 934, Carbopol 9~0, and a methyl ether of cellulose
available under the trade name Methocel MC, were used for
combination products. As shown in Table I, formulations 4
and 5, a fast degradation at the carbon-17 position of the
17-ester steroids was still observed.
Moreover, in a subsequent e~periment, a mixture of an
imidazole with hydrocortisone 17-valerate also showed rapid
hydrolysis even in pure petrolatum. Poor dispersibility is
considered the cause of the stability failure in the pure
petrolatum system (see Table I, formulation 6).
Since ester hydrolysis is known to be affected by pH,
the stability of an imidazole with a 17-ester steroid o/w
cream system adjusted to different pHs was studied. The
results ~Table II) show that simple pH ad~ustment will not
impart the required stability.
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131~
able II. Degradation rates of hydrocortisone 17-valerate
0.2% in the presence of 1% ~ulconazole nitrate
in USP XXI hydrophilic ointment (an o/w cream)
at ~5C i 2.0C at different pH.
pH k, day _gO~, daYs
2.10 2.10 x 10 S0
4.00 3.80 x 10 3 28
4.70 4.45 x 10 3 24
6.50 5.20 x 10 3 ~0
.
In-ordar to prevent the degradation of hydrocortisone
and its derivatives in topical formulations, it has been
proposed to use the steroid active ingredient in association
with certain stabilizers (e.g. EDTA, antioxidants) or to
reduce the amount of propylene glycol used in the
formulation8 10 Despite using stabilizer~ or reducing the
concentration of propylene glycol in the steroid
formulations of the prior art, it has not been po~ible to
obtain topical solutions, gels or creams of a combination
product having acceptable (two years or more) long term
stability.
To fulfill the unmet needs, it remained highly
desirable to obtain a combination of an imidazole antifungal
agent and a 17-ester antiinflammatory corticosteroid in a
topical dosage form which would be stable for at least two
years at room temperature (25 ~ 2C). It was an object of
the present invention to provide such a stable combinatlon
product from which the imidazole and 17-ester steroid would
_ g _
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... ., .. . . ~ .

~ 3 ~
be readily available ~or absorption by the skin. It was also
an object to provide a combination product formulation which
could be applied to the affected skin, e.g. the intertri-
gious area, without flowing onto the healthy parts of the
skin. This latter property would minimize the undesirable
side effects that might be caused by absorption through
surrounding tissue. Such a combination product then, would
not only provide fast relief of symptoms and the eradication
of the fungal infection but would also minimize the risk of
undesirable side effects.
It was a further ob;ect of the present invention to
provide a topical antifungal treatment which can effectively
provide fast relief of ~ymptoms and eradication of the
fungal infection while minimizing the risk of undesirable
side effects caused by high-potency and/or fluorinated
steroids.
It wa~ another object of the invention to provide
topical gel for~ulations of mid-potency 17-ester steroids
and imida~ole antifungal agents which pos~ess good
dispersibility and good physical and chemical stability
without refrigeration and without the naed or special
additives such as emulsifiers or surfactants or
antimicrobial preservatives.
It was anoth~r object of the invention to provide
topical gel formulations of 17-ester steroids and imidazoles
having other desirable qualities such as being cosmetically
acceptable and allowing accurate application of effective
amounts of the two active ingredients to the desired le~ion.
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... ..

11 3 ~
It was still another object of the invention to
provide topical gel formulations which enhance delivery of
a 17-ester steroid and imidazole to their respective target
sites, thereby ensuring that a maximum therapeutic
advantage could be achieved.
These and other objects of the present invention will
be more fully understood in the light o~ the specific
examples and description set forth below.
SU~ARY OF THE INVENTION
The present invention provides a stable gel
formulation for topical administration comprising a
therapeutically effective amount of a mixture of an
imidazole antifungal agent and a 17-ester steroid
antiinflammatory agent in a vehicle system comprising (a)
a co-solvent system for the imidazole and 17-ester steroid
consisting essentially of a lower alkanol in combination
with a dihydroxy alcohol or a trihydroxy alcohol, or a
mixture thereof and (b) an e~fective amount to cause
gelling of hydroxypropyl cellulose or hydroxyethyl
cellulose. 5UCh gel formulation may contai~ 0 to 20% (by
weight) water.
Thus in a broad embodiment the present invention
provides a stable gel formulation for topical
administration consisting essentially of (a) a
therapeutically effective amount of a mixture of at least
one antifungal agent selected from the group consisting of:
miconazole, miconazole nitrate, clotrimazole, clotrimazole
nitrate, enconazole, enconazole nitrate, sulconazole and
sulconazole nitrate with at least one steroid selected from
the group consisting of: the acetate, butyrate, valerate
and propionate 17 esters of hydrocortisone, betamethasone,
cortisone and prednisone, lb) a solvent system consisting
essentially of a lower alkanol in combination with a
dihydroxy alcohol or a trihydroxy alcohol or a mixture
_9
~ .

~3~a~
thereof, (c) an effective amount of at least one gelling
agent selected form the group consisting of hydroxylpropyl
cellulose and hydroxyethyl cellulose, and (d) water in an
amount up to about 20~ by weight, said formulation having
a pH in the range of from about 3 to about 5.
In another embodiment the invention provides a stable
gel formulation for topical administration consisting
essentially of (a) from about 0.2-2% by weight of one or
more imidazole antifungal agents selected from the group
consisting of micona~ole, miconaxole nitrate, clotrimazole,
clotrimazole nitrate, econazole, econazole nitrate,
sulconazole and sulconazole nitrate; (b) from about 0.01%-
2.5% by weight of and at least one 17-ester steroid
selected from the group consisting of the 17-ester
acetates, ~utyrates, valerates, and propionates of
hydrocortisone, betamethazone, cortisone, and prednisone;
(c) from about 30-65% by weight of a lower alkanol solvent
for the imidazole and 17-ester steroid; (d) from about 0-
45% by weight of a dihydroxy alcohol solvent for the
imidazole and 17-ester steroid; (e) from about 0-40% by
weight of a trihydroxy alcohol solvent for the imidazole
and 17-ester steroid; ~f) about 20% by weight or less of
water; and (g) from about 0.1-5% by weight of a gelling
agent selected from hydroxypropyl cellulose and
hydroxyethyl cellulose, said formulation having a pH in the
range of about 3 to about 5.
In still a further embodiment the invention provides
a method of stabilizing a topical gel formulation
containing an imidazole gel and at least one 17-ester
steroid and having a pH in the range of ~rom about 3 to
about 5 comprising the step of incorporating into the
formulation a combination consisting essentially of
(a) from about 30 to about 65% by weight of a lower
alkanol with about 0 to about 0 to 85% of at least one
polyol selected from the group consisting of dihydroxy
alcohols and trihydroxy alcohols; and
- ll(a) -

~3~ 9~
(b) a suitable gelling amount of hydroxyethyl
cellulose or hydroxypropyl cellulose.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 represents a comparison of the skin penetration
rates of hydrocortisone 17-valerate in aqueous and
anhydrous gel formulations of the present invention with
the rates in hydrocortisone 17-v,alsrate cream and ointment
formulations.
- ll~b) -
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FIG. 2 represents a comparison of the skin penetration rates
of ~ulconazone nitrate in aqueous and anhydrou~ gel
formulations of the present invention with the rates in
sulconazone nitrate creams and aqueous solutions.
DETAILED DESCR:[PTION
It was discovered during experiments carried out by the
present inventors that the stability of formulations
containing both imidazoles and 17-ester steroids seemed to
be dependent on dispersibility. For example, in cream or
solution formulations, the stability improved as the
concentration of water in the ormulation decreased. Also,
viscous creams or pure petrolatum bases did not provide good
stability. Thus, only cream formulations with higher
solvency of the 17-ester steroid and imidazole can provide
satisfactory stability due to their better dispersibility
which reduces the interaction of these two agents.
Imidazoles are insoluble in most common aqueous and
non-aqueous solvents including water. They can be
solubilized in aqueous vehicles onl~ if the vehicles contain
high concentrations of surfactants (greater than 10%). With
high surfactant concentration, however, 17 ester steroids
are subject to rapid hydrolysis.
It has been discovered by the present inventors that
the only vehicles in which 17-ester steroids and imidazoles
are soluble, evenly dispersed and stable are certain organic
solvents. More particularly, the two active components must
be dissolved in a co-solvent system consisting essentially
of a lower alkanol in combination with a dihydroxy alcohol
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~3l~a~
or trihydroxy alcohol or mixtures thereof. Examples ofsuitable dihydroxy alcohols are hexanediols such as
2-ethyl-1,3-hexanediol and glycols such as ethylene glycol,
propylene glycol and 1,3-hutylene glycol. The most
preferred glycol is propylene glycol. Examples of
trihydroxy alcohol are hexanetriols such as 1,2,6-hexane-
triol. Lower alkanols include such alcohols as methanol,
ethanol, propanol, isopropanol, butanol, and the like. The
most preferred lower alkanols are isopropanol and ethanol,
or mixtures thereof. Preferably, the dihydroxy alcohol is
present in an amount of 0 to 45% by weight and/or
trihydroxy alcohol is present in an amount of from about 0
to 40% by weight and the lower alkanol in an amount of from
about 30-65~ by weight. The skin penetration rates of
imidazole and steroid can be adjusted by varying the
concentrations of co-solvent system in the formulation.
Higher concentrations of alcohol ~ive a higher depot effect
and an enhanced skin penetration rate. However, higher
alcohol concentrations also increase skin irritation with
concentrations over about 60% by weight resulting in
excessive irritation. Therefore, a balance has to be
maintained between a desire to enhance skin penetration
rates of the active components, particularly the imidazole
component, and a desire to achieve a non-irritating product.
As indicated in Table III, the formulations of the
present invention enhance the stability of 17-ester steroids
almost 5-40 times in term~ of tgo%. The substantial
stability enhancement seen here is in startling co~trast to
the instability found in other cream and gel formulations.
With 10% overage of 17-ester steroid, the stability profile
for the formulations of the present invention supports a 2
- 13 -
..... . . . ... .. .. . ...... . . .

13~9~
year expiration dating period at room temperature. All tgo%values given in Table III below were determined at 25C
2C.
able III. Degradation rates of 17-ester hydrocorti~one in
the presence of 1~ imidazoles in the present
invention gel formulations at 25C i 2.0C.
1) R&D Product No. 30159-B-l9-A(FN7-969-06~
Ingredient ~ w/w
Sulconazole nitrate 1%
Hydrocortisone 17-valerate Ø2%
SD Alcohol 40 50%
Propylene glycol 30%
PPG-5-Ceteth-20 12.3%
Isopropyl myristate 5%
Hydroxypropyl cellulose 0.9%
Salicylic acid 0.5%
Ascorbyl palmitate 0.1%
k, day i tgo%,days
FN7-969-06
Chemical
Stability result 2.39 x 10 440
- 14 ~

~3~9~
2) R&D Product No. 30159-B-23-A(FN7-994-02)
Inqredient ~
Sulconazole nitrate 1%
Hydrocortisone 17-valerate 0.2%
SD Alcohol 40 35%
Propylene glycol 40%
PPG-5-Ceteth-20 12.3%
Water for production 5%
Isopropyl myristate 5~
Hydroxypropyl cellulose 0.9%
Salicylic acid 0.5%
Ascorbyl palmitate 0.1%
k, day 1tg~%,days
EN7-994-02
Chemical
Stability result 2.20 x 10 4477
3) (ErN7-944-18)
Inaredient X w/w
Miconazole nitrate 1%
Hydrocortisone 17-valerate 0.2%
SD ~lcohol 40 50%
Propylene glycol 30%
PPG-5-Ceteth-20* 12.45%
- 15
* Trademark

~3191~tt~
3) (FN7-944-18)
Inqredient ~ w/w
Isopropyl myristate 5%
Hydroxypropyl cellulose 0.75%
Salicylic acid 0.5%
Ascorbyl palmitate 0.1%
k, day 1 tgo%,days
FN7-994-18
Chemical -4
-Stability result 2.08 x 10 - 506
4) (FN7-944-l9)
Inaredient % w/w
Econazole nitrate 1%
Hydrocortisone 17-valerate 0.2%
SD Alcohol 40 50%
Propylena glycol 30%
PPG-5-Ceteth-20 12.45%
Isopropyl myristate 5%
Hydroxypropyl cellulose 0.75%
Salicylic acid 0,5%
Ascorbyl palmitate 0.1%

13~ 91~
_ .
k, day-1t9o%~days
FN7-994-19
Stabil;ty result 3.33 x 10 4 316
5) (FN7-944-201
Inqredient ~ w/w
Clotrimazole 1%
Hydrocortisone 17-valerate 0.2%
SD Alcohol 40 50%
Propylane glycol 30%
PPG-5-Ceteth-20 12.45%
Isopropyl myristate 5%
Hydroxypropyl cellulose 0.75%
Salicylic acid 0.5%
Ascorbyl palmitate 0.1%
k, day 1 tgO%,days
FN7-944-20 .
Chemical -4
Stability result 2.42 x 10 _
6) (FN8-1094-20)
Inqredient ~ w/w
Sulconazole nitrate 1%
Hydrocortisone 17-valerate 0.2%
- 17 -
-
. ~.. ..... ~,.. - - -

~319~
SD Alcohol 40 50%
2-Ethyl-1,3-Hexanediol 22%
1,2,6-Hexanetriol 15%
Isopropyl myristate 5%
Water 4.99
Hydroxypropyl cellulose o.9%
Salicylic acid 0.5%
BHT 0.2%
BHA 0.2%
Disodium EDTA 0.01
Q.S. NaOH lN adjust pH to 4.0
_
k, day~lt9o%~days
FN8-1094 20
Chemical
Stability result 3.33 x 10 4 316
In addition to the two active components and the
co-solvent system, there is also required in the present gel
ormulations an effective amount to cause gelling of either
hydroxypropyl cellulose or hydroxyethyl cellulose. As noted
previously, other gelling agents such as methyl cellulose
and carboxy vinyl polymer gels gave unstable gel
ormulations. Generally the gelling agent will be present in
an amount of from about 0.1 to 5%.
A general formula encompassing gel formulations within
the scope of the present invention is set forth below. All
amounts are in weight percent.
- 18 -
.

13
General Gel Formula in ~ w/w
Component Amount, ~w/w
Imidazole antifunyal agent 0.2-2.0
17-E~ter steroid 0.01-2.5
Lower alkanol 30-65
Dihydroxy alcohol 0-45
Trihydroxy alcohol 0-40
Gelling agent 0.1-5
Water 0-20
Emollient 0-30
Fragrance 0-2.0
- Preservative 0-1.5
Both anhydrous and hydrous gel formulations are
encompassed by the present invention. Anhydrous ormulations
contain as essential components the two active ingredients,
the dihydroxy alcohol and/or the trihydroxy alcohol, the
lower alkanol and gelling agent. They may also contain
other components conventionally amployed in gel
formulations, e.g. emollients such as isopropyl myristate,
PPG-5-ceteth-20, PPG-10 methyl glucose ether, PPG 20 methyl
glucose ether, PG dioctanate, methyl gluceth-10, methyl
gluceth-20, isodecyl neopentanoate, glycerin, mineral oil,
etc.~preferably in an amount of up to about 30%, more
preferably about 5-30%), and antioxidants, e.g. ascorbyl
palmitate, BHT, BHA, etc., chelating agents such as EDTA,
and other preservatives such as salicylic acid, fragrances
(up to about 2%), dyes, skin penetration enhancers, etc.
-- 19 --

13~
The preferred gsl formulations of the present
invention, both agueous and anhydrous, contain an emollient
component. The most preferred emollients are isopropyl
myristate, PPG-5-ceteth-20, PPG-20 methyl glucose ether, or
a mixture thereof.
A preferred anhydrous gel formulation of the present
invention comprises sulconazole nitrate 1% and
hydrocortisone 17-valerate 0.2% glel of the following
composition:
Com~onent Amount, ~ w/w
sulconazole nitrate
hydrocortisone 17-valerate 0.2
ethyl alcohol 61.3
propylene glycol 25
isopropyl myristate 5
hydroxypropyl cellulose 2
salicylic acid 0.5
PPG-5-ceteth-20 5
Another preferred anhydrous gel formulation i8 that of
the formula:
ComPonent Amount, ~ w/w
sulconazole nitrate
hydrocortisone 17-valerate 0.2
ethyl alcohol 50
propylene glycol 30
PPG-5-ceteth-20 17.45
- 20 -

13~9~
hydroxypropyl cellulose 0.75
salicylic acid 0.5
ascorbyl palmitate 0.1
Hydrous (or aqueous) gel formulations of the present
invention contain, in addition to the components described
above for the anhydrous formulations, water in an amount up
to about 20%, m~st preferably in an amount of from about 5
to 10%. In the hydrous gel formulations it is necessary that
the pH of the formulation be within the range of about 3-5.
This may be accomplished, if necessary, by use of
conventional pharmaceutically acceptable acids or bases.
A preferred aqueous gel formulation of the present
invention has the following formula:
Component Amount, ~ w/w
sulconazole nitrate
hydrocortisone 17-valerate 0.2
ethanol 61.3
propylene glycol 20
water lO
isopropyl myristate 5
hydroxypropyl cellulose 2
salicylic acid 0.5
The gel-form compositions of the present invention may
be formulated by the conventional mixing of the components
described above. To illustrate preparation of a hydrous
formulation, ethanol, propylene glycol and water are mixed
together to form the co-solvent system. Salicylic acid,
- 21
.... .. . .... . .

~319~ 0~
emollient, preservative and/or antioxidant are dissolved
into the co-solvent system. Twenty-five percent of the
solvent system i8 used to dissolve sulconazole nitrate.
Another 25% of solvent is used to dissolve hydrocortisone
17-valerate. Gelling agent i~ added the remaining 50% of
solvent and stirred vigorously for more than 45 minutes to
hydrate the gel. After completion of the gelling process,
sulconazole nitrate solution and hydrocortisone 17-valerate
solution are added separately into the gel solution to form
the final product.
The gel compositions of the present invention are clear
and stable with a shelf life of two years or more at room
temperature when a 10% overage of active ingredients is
used.
It has been unexpectedly found that the gel
formulations of the present invention also provide desirable
skin penetration rates of imidazole and 17-ester steroid.
For example, the skin penetration rate of 17-ester sterold
in the combination product can be adjusted to the same level
as exhibited by existing 17-ester steroid ointments and
creams, while much higher levels of imidazole antifungal
agent can be delivered as compared to the presently
available imidazole solutions and creams. (see FIG. 1 and
FIG. 2). This unique feature of the gel formulation enables
it to provide an effective level of imidazole against fungal
infection while still maintaining a safe level of 17-ester
steroid. FIG. 1 demonstrates that, when compared to marketed
- 22 -
.. , . ~ , . . ~ .. .. . . .

13~91~
hydrocortisone 17-valerate crea~s and ointments, the hydrous
gel of the present invention achieves at least an equal skin
penetration of the 17-ester steroid relative to such
products while the anhydrous gel achieves a somewhat
enhanced effect. FIG. 2 shows that:, when compared to
solution and cream formulations of sulconazole nitrate, both
the hydrous and anhydrous gel formulations of the present
invention achieve substantially increased skin penetration
rates of the imidazole antifungal agent. As mentioned
previously, the skin penetration rate in the gel
formulations of the present invention can be controlled by
the percentage of lower alkanol in the formulation, with
higher alkanol concentrations giving higher ~kin penetration
rates. We have found that the lower alkanol should be
employed in the amoùnt of from about 30-65% and the
dihydroxy alcohol in an amount of from about 0-~5% and/or
the trihydroxy alcohol in an amount of from 0-40% for
optimum stability, skin penetration effects and comfort,
i.e. lack of irritation.
Topical treatment regimens according to the practice of
this invention involve applying the compositions herein
directly to the skin at the situs of the fungal infection.
The rate of application and duration of treatment will
depend upon the severity and nature of the condition, the
response of a particular patient, and related factors within
the sound medical judgment of an attending physician or the
patient. In general, the gel formulation is applied at least
daily, preferably twice or three times per day, until the
eradication of the fungal infection.
- 23 -
-

The following non-limiting examples illustrate the
pharmaceutical compositions of the present invention.
Example 1
Preparation of Aqueous 1~ Sulconazole Nitrate/0.2X
Hydrocortisone-17-valerate Gel
~ w/w
sulconazole nitrate
hydrocortisone 17-valerate 0.2
ethanol 50
propylene glycol 33
isopropyl myristate 5
water 5
PPG-5-ceteth-20 4.2
hydroxypropyl cellulose 0.9
salicylic acid 0.5
ascorbyl palmitate 0.2
q.s. NaOH lN adjust pH to 4.0
Ethanol (5.1 kg), propylene glycol (3.3 kg) and
isopropyl myristate (0.5 kg3 were added to a suitable mixing
vessel. Then, with rapid mixing 0.420 kg of PPG-5-Cetech-20
was added and the reaction mixture was mixed until uniform.
With rapid mixing, 0.020 kg ascorbyl palmitate, 0.105 kg
sulconazole nitrate and 0.050 kg salicylic acid were slowly
added and mixing was continued until all solids were
dissolved. Into a separate premix vessel 0.075 kg water was
added and then 0.004 kg NaOH was slowly added with mixing
until the reaction mixture was uniform. To the original
mixing vessel, there was then added 0.400 kg water and the
- 24 -
... .. .. . .. . ~, ,

131 s~a~
NaOH solution with continued mixing for 5 to 10 minutes
until a uniform consistency was achieved. The pH of the
reaction mixture wa~ determined to be 4.1. To the main
vessel 0.025 kg water was added followed by 0.022 kg
hydrocortisone 17-valerate. Rapid mixing was continued for
about 15 minutes. Then, with rapid mixing, 0.090 kg
hydroxypropyl cellulose was added and the reaction mixture
was mixed rapidly for about two hours to obtain the desired
gel.
Example 2
~ w/w
sulconazole nitrate
hydrocortisone 17-valerate0.2
ethanol 50
propylene glycol 30
PPG-5-Ceteth-20 12.3
isopropyl myristate 5
hydroxypropyl cellulose 0.9
salicylic acid 0.5
ascorbyl palmitate 0.1
~xample 3
~ w/w
sulconazole nitrate
hydrocortisone 17-valerate0.2
ethanol 35
propylene glycol 40
PPG-5-Ceteth-20 12.3
water 5
isopropyl myristate 5
- 25 -
. .

1319~
Example 3 (cont.)
~ w/w
hydroxypropyl cellulose 0.9
salicylic acid 0.5
ascorbyl palmitate 0.1
Example 4
~ w/w
miconazole nitrate
hydrocortisone 17-valerate 0.2
ethanol 50
propylene glycol 30
PPG-5-Ceteth-20 12.45
isopropyl myristate - 5
hydroxypropyl cellulose 0.75
salicylic acid 0.5
ascorbyl palmitate 0.1
Example 5
~ w/w
econazole nitrate
hydrocortisone 17-valerate 0.2
ethanol 50
propylene glycol 30
PPG-5-Ceteth-20 12.45
isopropyl myristate 5
hydroxypropyl cellulose 0.75
salicylic acid 0.5
ascorbyl palmitate 0.1
ExamDle 6
~ w/w
sulconazole nitrate
hydrocortisone 17-valerate Q.2
- 26 -
.- ^ 7

13191 ~
Example 6 (cont.)
~ w/w
isopropanol 50
propylene glycol 30
PPG-5-Ceteth-20 12.45
isopropyl myristate 5
hydroxyethyl cellulose 0,75
salicylic acid 0,5
ascorbyl palmitate 0.1
Example 7
~ w/w
sulconazole nitrate
hydrocortisone 17-valerate 0.2
ethanol 50
2-ethyl-1,3-hexanediol 22
propylene glycol 15
isopropyl myristate 5
water 4 99
hydroxypropyl cellulose 0.9
salicylic acid 0.5
BHT 0.2
BHA 0.2
disodium EDTA 0.01
g.s. NaOH lN adjust to pH 4.0
Example 8
% w/w
sulconazole nitrate
hydrocortisone 17-valerata 0.2
ethanol 50
1,2,6-hexanetriol 27
2-ethyl-1,3-hexanediol 7.5
- 27 -

1319~
Example 8 (con-t.~
~ w/w
i sopropyl myri state 7 . 5
PPG-20 methyl glucose ether 5
hydroxypropyl cellulose 0.9
salicylic acid 0.5
BHT 0.2
BHA 0.2
- 28 -
.

13191~3~
Reference
1. Wortzel, M. Y., H., A double-blind study comparing the
superiority of a combination anti-fungal
(clotrimazole/steroidaltbetamethasone dipropionate))
product Cutis 30: 258 (1982).
2. Katz, H. I., Bard, J., Cole, G. W., Fischer, S.,
McCormick, G. E., Medansky, R. S., Nesbitt, L. T., and
Rex, I. H., SCH 370 (clotrimazole-betamethasone
dipropinate) cream in patients with tinea cruri or
tinea corporis. Cutis, 34(2), 183-8(1984).
3. Bruice, T. C., and Schmir, G. L., Arch. Biochem.
Biophys. 63: 484(1956).
4. Bruice, T. C., and Schmir, G. L., Imidazole catalysis.
I. The catalysis of the hydrolysi 5 of phenyl acetates
by imida701e., J. Am. Chem., Soc., 79: 1663-9(1957).
5. Bruice, T. C., and Schmir, G. L., Imidazole catalysi
II. The reaction of substituted imidazoles with phenyl
acetates in aqueous solution., J. Am. Chem. Soc., 80:
148-56(1958).
6. Bender, M. L., and Turnquest, B. W., General Basic
catalysis of est~r hydrolysis and its relationship to
enzymatic hydrolysis., J. Am. Chem. Soc., 79:
1656-62(1g57~.
7. Richter Gedeon Vegy, Stable antifungal and
anti-inflammatory ointment, JP 76576.
- 29 -

~3~9~0~
8. Yip, Y. W., Po, L. W., and Irwin, W. J., Kinetics ofdecomposition and formulation of hydrocortisone
butyrate in semi-aqueous and gel systems, J. Pharm.
Sci., 72, 776-81(1983).
9. Gupta V. D., Effect of vehicles and other active
ingredients on stability of hydrocortisone., J. Pharm.
Sci., 67:299(1978).
lO. Hansen, J. and Bundgaard, H., Studies on the stability
of corticosteroids V. The degradation pattern of
hydrocortisone in aqueous solution., Int. J. Pharm., 6:
307-19(1980~.
- 30 -
. .